Atherosclerosis is the leading cause of morbidity and mortality in the United States and is characterized as a systemic, progressive disease process in which the arterial wall thickens through a process of inflammation, oxidative stress, and dyslipidemia. This process leads to plaque formation and flow limitation in the vessel lumen. The sudden rupture of this arterial plaques lead to thrombosis and sudden occlusion of the vessel and ultimately, in myocardial infarction, stroke, or limb injury. Future development of systemic or localized therapies for atherosclerosis will likely depend upon a more detailed understanding of plaque development. Improving the understanding of plaque development will require in-vivo monitoring of morphological, biochemical and functional/molecular changes accompanying plaque formation and/or response to treatments. Unfortunately, there is no current imaging modality (neither non-invasive nor intravascular) that can provide such level of plaque characterization. We propose to develop a novel imaging technology that will enable high-speed in vivo intravascular imaging of plaque morphology, biochemical composition and molecular activity, by combining optical coherence tomography (OCT) with endogenous and exogenous fluorescence lifetime imaging (FLIM). Intravascular OCT offers high-resolution intravascular imaging of atherosclerotic plaque. FLIM has been shown to be far less susceptible to artifacts endemic to in vivo imaging than steady-state fluorescence. FLIM imaging of endogenous plaque fluorescence allows quantifying plaque biochemical content. FLIM imaging of exogenous fluorescent tags labeling multiple molecular targets will allow monitoring plaque molecular activity. To develop and validate this novel intravascular imaging modality, the following three specific aims are proposed. Aim 1: To integrate OCT with endogenous FLIM imaging for non-destructive identification of the different types of atherosclerotic plaques. Aim 2: To design and build a high-speed optical imaging system, including a dual-mode fiber catheter, suitable for in vivo intravascular simultaneous and coregistered OCT and endogenous/exogenous FLIM imaging of atherosclerotic plaques. Aim 3: To quantify the capacity of the OCT/FLIM intravascular imaging system to monitor over time plaque morphology, biochemical composition and molecular activity in-vivo. We believe that the resulting intravascular imaging technology will enable comprehensive understanding of plaque development and may ultimately help facilitate the development of a cure for atherosclerosis.